Erythro-1,2-1-pentanones

ABSTRACT

Erythro-1,2,3-triphenyl-1-pentanones of Formula 1 ##STR1## wherein R 1  may be a dimethylamino, diethylamino, piperidin-1-yl- or pyrrolidin-1-yl group and R 2  represents a hydrogen atom, a methoxy or hydroxy group, and their pharmacologically acceptable salts, have a pronounced antiestrogenic effect and are suitable for the treatment of hormone-dependent tumors. 
     They may be prepared by reacting 1,2-diphenyl-ethanone of Formula 2 ##STR2## wherein R 1  is as set forth in Formula 1 and R 2  represents a hydrogen atom or a methoxy group, with sodium hydride in anhydrous dimethyl-formamide, isolating after conversion with 1-chloro-1-phenylpropane, the erythro form from the reaction product and possibly releasing the hydroxy group from the methoxy group by selective cleavage with hydrobromic acid.

This is a continuation of application Ser. No. 376,942, filed May 10,1982 and now abandoned.

BACKGROUND OF THE INVENTION

The invention concerns 1,2,3-triphenyl-1-pentanone derivatives which areeffective in treating estrogen-dependent tumors.

It is disclosed in British Pat. No. 1 013 907 that 1,1,2-triphenylalkenederivatives may possess antiestrogenic properties and are thus suitablefor the treatment of hormone-dependent tumors. In addition to thesecompounds, a series of further nonsteroid, antiestrogenic activeingredients has become known, the basic structures of which are of thetriarylalkene type.

It is an object of this invention to provide new and effective compoundsexhibiting high antiestrogenic activity which are thus useful in thetreatment of estrogen-dependent tumors.

It is a further object of this invention to provide a compound havinghigh binding affinity to the estradiol receptor of the uterus.

SUMMARY OF THE INVENTION

It has now been found surprisingly that antiestrogenically effectivecompounds are also present in the heretofore unknown class of the1,2,3-triphenyl-1-pentanones of formula 1. ##STR3## wherein R¹ may be adimethylamino, diethylamino, pyrrolidin-1-yl or a piperidin-1-yl group,and R² represents a hydrogen atom, a methoxy or a hydroxy group. Alsoeffective are their pharmacologically acceptable salts.

As shall be shown hereinafter, the compounds claimed have a high bondingaffinity, in their erythro form, to the estrogen receptor. Based ontheir high specific activity, the compounds claimed exhibit a pronouncedautiuterotropic activity, which is of decisive importance for anymammatumor inhibiting activity.

The invention further concerns a process for the preparation ofcompounds of the general formula 1, wherein 1,2-diphenylethanones of thegeneral formula 2 ##STR4## wherein R¹ is defined as in general formula 1and R² is a hydrogen atom or a methoxy group, are reacted in anhydrousdimethylformamide with sodium hydride to form a mixture of the erythroand threo forms of the 1,2,3-triphenyl-1-pentanone. The erythro form isisolated by means of crystallization after reaction with1-chloro-1-phenylpropane. Compounds of the general formula 1, wherein R²is a hydroxy group, are obtained by subjecting the methoxy-substitutedcompounds of the general formula 1 to a selective methylether cleavage.

DETAILED DESCRIPTION OF THE INVENTION

1,2-diphenylethanones may be prepared in the following manner.

Compounds of the general formula 3

    R.sup.1 --CH.sub.2 CH.sub.2 Cl                             (3)

wherein R¹ may be a dimethylamino, diethylamino, pyrrolidin-1-yl or apiperidin-1-yl group, are converted in the presence of alkali withphenol to ethers of the general formula 4 ##STR5## wherein R¹ is asdefined above. Compounds of the general formula 4 may be converted, in aFriedel-Crafts reaction with phenylacetic acid chlorides of the generalformula 5 ##STR6## wherein R² represents a hydrogen atom or a methoxygroup, into the 1,2-diphenylethanones of the general formula 2.Following the action of sodium hydride on compounds of general formula 2and subsequent conversion with 1-chloro-1-phenylpropane, compounds ofgeneral formula 1 are obtained, wherein R² represents a hydrogen atom ora methoxy group.

Crystallization from dilute methanol yields the compounds in their pureerythro form.

When the methoxy derivatives of general formula 1 are heated underreflux with a solution of hydrobromic acid, they are cleaved intocompounds of general formula 1, wherein R² represents a hydroxy group.

The following compounds are exemplary of the 1,2,3-triphenyl-1-pentanonecompounds claimed:

                  TABLE 1                                                         ______________________________________                                         ##STR7##                                                                     No. of Compound                                                                          R.sup.1      R.sup.2 Melting Point                                 ______________________________________                                        1          (CH.sub.3).sub.2 N                                                                         H       129-131° C.                            2          (C.sub.2 H.sub.5).sub.2 N                                                                  H       108-109° C.                                        ##STR8##    H       128° C.                                4                                                                                         ##STR9##    H       125° C.                                5          (CH.sub.3).sub.2 N                                                                         OCH.sub.3                                                                             88-89° C.                              6          (CH.sub.2 H.sub.5).sub.2 N                                                                 OCH.sub.3                                                                             89-90° C.                              7                                                                                         ##STR10##   OCH.sub.3                                                                             96-98° C.                              8                                                                                         ##STR11##   OCH.sub.3                                                                             98-99° C.                              9          (CH.sub.3).sub.2 N                                                                         OH      200° C.                                10                                                                                        ##STR12##   OH      181-182° C.                            ______________________________________                                    

The erythro and threo forms of 1,2,3-triphenyl-1-pentanone derivativesof general formula 1 are clearly different in their proton resonancesignals of methyl protons in the pentanone chain. The signals of theerythro form are shifted to the high field in relation to the threoform, which has also been found with hexestrol derivatives. (R. Gaswami,S. G. Harsy, D. F. Heiman and J. A. Katzenellenbogen, J. Med. Chem. 23,1002 (1980)).

A high antiestrogenic activity of the erythro forms of the1,2,3-triphenyl-1-pentanone derivatives of general formula 1 wasdetermined. They are thus therapeutically useful in the treatment ofestrogen-dependent tumors.

The determination of the binding affinity to the estradiol receptor waseffected by means of the rabbit uterus cytosol. The compounds claimedexhibit high bonding affinities.

The measurement of the antiuterotropic action was effected following athree-week treatment with the active ingredient of sexually mature,female rats. The compounds claimed exhibit pronounced antiuteroptropiceffects.

The tumor inhibiting action was measured following a four-week treatmentwith the active ingredient on female rats, with mammatumors inducedpreviously with 7,12-dimethylbenz(a)anthracene. The compounds exhibit astrong inhibition of the growth of tumors.

The compounds of the invention thus represent a valuable addition to therange of available medicines and may be employed in the treatment ofmalignant mammatumors.

The invention further includes medicines containing a compound ofgeneral formula 1 as the active ingredient, in addition to the usualpharmaceutical carriers and auxiliary substances.

The compounds are preferably administered orally. The daily oral dosageis usually from about 0.01 to about 0.2 g, preferably 0.02 to 0.1 g.However, it may be necessary in certain cases to deviate from the abovecited doses, as a function of individual response to the drug or themanner of its formulation and the frequency at which the drug isadministered. Thus, in certain cases it may be sufficient to administerless than the aforementioned minimum dosage, while in other cases theaforementioned upper limit must be exceeded. When larger amounts areadministered, it may be advantageous to divide them over a day inseveral smaller, individual doses. The active ingredients may becompounded prior to oral administration, for example in capsules,tablets or as dragees.

The drugs may be processed into tablets or dragees cores by mixing theactive ingredient with solid, powdered carrier substances, such asmicronized cellulose, potato or corn starch, with additions such assodium citrate, calcium carbonate and binders such as polyvinylpyrrolidone, gelatin or cellulose derivatives, possibly with theaddition of lubricants such as magnesium stearate, sodium lauryl sulfateor polyethylene glycols. For oral administration, they may be mixed withflavor enhancers.

Other suitable forms for administration of the drug are coated capsules,for example of hard gelatin, or sealed soft gelatin capsules with aplasticizer, such as glycerine. The coated capsules contain the activeingredient preferably in the form of granulates, and may be mixed withfillers, such as potato starch or amylopectin, cellulose derivatives orhighly dispersed silica. In soft gelatin capsules the active ingredientis dissolved or suspended preferably in suitable liquids, for example invegetable oil or liquid polyethylene glycols.

The invention shall become more apparent from the examples which follow.These examples are given with the understanding that they are intendedto illustrate the invention but are not intended to act as a limitationon the scope of the present invention.

EXAMPLE 1 1-(4'-(2-dimethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanone

Preparation of Starting Materials

(a) Preparation of1-(4'-(2-dimethylaminoethoxy)-phenyl-2-phenyl)-1-ethanone

20.2 g (0.1 mole) N,N-dimethyl-2-phenoxyethylaminohydrochloride and 15.5g (0.1 mole) phenylacetic acid chloride are suspended in 350 mlanhydrous methylene chloride and reacted at room temperature with 26.7 g(0.2 mole) anhydrous aluminum chloride in portions. After the additionis completed, the reaction solution is heated for one hour to refluxtemperature, then poured on ice and made alkaline with 25% sodiumhydroxide. The organic phase is separated, washed to attain a neutralpH, and dried over sodium sulfate. The solvent is removed by vacuum andthe residue crystallized from petroleum ether. Colorless crystals with amelting point of 54° to 55° C. were obtained in a yield of 17.0 g (60%);R_(f) =(0.25 HCCL₃ /MeOH(95/5)).

C₁₈ H₂₁ NO₂ (283.4)

¹ H-NMR-spectrum (CDCl₃).sup.(1) : 2.33 s (6) N(CH₃)₂ ; 2.73 t (2) CH₂-N (J=6.0); 4.10 t (2) OCH₂ (J=6.0); 4.20 s (2) CH₂ ; 6.93 d (2)aromatic-H (J=9.0); 7.28 s (5) aromatic-H; 8.00 d (2) aromatic-H(J=9.0).

(b) Preparation of 1-chloro-1-phenylpropane

13.6 g (0.1 mole) of 1-phenylpropan-1-ol are taken up in petroleum etherand are reacted at -20° C. with hydrochloric acid until theprecipitation of water is terminated. Subsequently, the organic phase iswashed neutral with water, dried (sodium sulfate) and the petroleumether removed in a vacuum. The bright yellow, thermolabile oil is usedwithout further purification. The oil has an R_(f) of 0.8 (CH₂ Cl₂) andis attained in a yield of 13.1 g (85%).

C₉ H₁₁ Cl (154.67)

¹ H-NMR spectrum (CDCl₃): 0.97 t (3) CH₃ (J=7.0); 1.73 to 2.40 m (2) CH₂; 4.77 t (1) CH (J=7.6); 7.35 s (5) aromatic H.

Preparation of a compound of the present invention

(c)erythro-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanone

To a suspension of 150 ml anhydrous dimethylformamide and 2.4 g (0.1mole) sodium hydride, a solution of 28.3 g (0.1 mole)1-(4'-(2-dimethylaminoethoxy)-phenyl)-2-phenyl-1-ethanone in 150 mlanhydrous dimethylformamide is added slowly, in drops, at 20° C. andunder N₂ atmosphere. Following the completion of the addition, themixture is allowed to react for one-half hour at room temperature andthen a solution of 18.5 g (0.12 mole) 1-chloro-1-phenylpropane in 50 mlanhydrous dimethylformamide is added in drops, at room temperature.After 2 hours the reaction solution is quenched with water and taken upin ethylacetate. The organic phase is washed with water to obtain aneutral pH, dried over sodium sulfate, and condensed in a vacuum. Theerythro form may be crystallized out of a methanol/water solution.Colorless crystals with melting points of 129° to 131° C. and R_(f) =0.3(CHCl₃ /MeOH (9/1)) are obtained in a yield of 18.0 g (45%).

C₂₇ H₃₁ No₂ (401.6) Calculated: C 80.76, H 7.78, N 3.49. Determined: C80.93, H 7.88, N 3.46.

Molecular weight: 401 (determined by mass spectrometry).

IR spectrum (KBr): ν (C=O) 1665 cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.57 t (3) CH₃ (J=6.0); 1.10 to 1.77 m (2) CH₂; 2.28 s (6) N(CH₃)₂ ; 2.67 t (2) CH₂ -N (J=5.0); 3.17 to 3.80 m (1) CH;4.00 t (2) OCH₂ (J=5.0); 4.90 d (1) CH--C═O (J=11.8); 6.80 d (2)aromatic H (J=9.0); 7.00 to 7.63 m (10) aromatic H; 7.80 d (2)aromatic-H (J=9.0).

(d) Preparation oferythro-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanonehydrochloride

Hydrochloric acid is passed under cooling with ice into a solution of40.1 gerythro-1-(4'-2-dimethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanone in250 ml ether, until the ether solution clearly reacts in an acidicmanner. The hydrochloride precipitated is suctioned off and dried.Colorless crystals with a melting point of 190°-191° C. are recovered;yield is quantitative.

(e) Preparation ofthreo-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanone

The mother liquor of the crystallizate of Example 1c is purified bycolumn chromatography (silica gel; solvent: CHCl₃ /MeOH (9/1)). Thethreo form is thereby obtained as a colorless oil with a slight yield(R_(f) =0.3 (CHCl₃ /MeOH) (9/1); yield: 1.6 g (4%)).

¹ H-NMR spectrum (CDCl₃): 0.72 t (3) CH₃ (J=6.4); 1.10 to 2.00 m (2) CH₂; 2.30 s (6) N(CH₃)₂ ; 2.73 t (2) CH₂ -N (J=5.0); 3.20 to 3.80 m (1) CH;4.07 to (2) OCH₂ (J=5.0); 4.73 d (1) CH--C═O (J=10.6); 6.63 to 8.20 m(14) aromatic H.

EXAMPLE 2 Preparation oferythro-1-(4'-(2-diethylaminoethoxy)-phenyl)-2,3-diphenyl-1-pentanone

31.1 g (0.1 mole) of1-(4'-(2-diethylaminoethoxy)-phenyl)-2-phenyl-1-ethanone (melting point35°-36° C., from petroleum ether) prepared in a manner similar toExample 1(a), are reacted as described in Example 1(c). Colorlesscrystals with a melting point of 108°-109° C. (petroleum ether) result;yield 6.0 g (14%); R_(f) =0.3 (CHCl₃ /MeOH (9/1));

C₂₉ H₃₅ NO₂ (429.6) Calculated: C 81.08 H 8.21 N 3.26. Determined: C80.96 H 8.15 N 3.20.

Molecular weight: 429 (determined by mass spectrometry).

IR spectrum (KBr) ν (C═O) 1670 cm¹.

¹ H-NMR spectrum (CDCl₃): 0.57 t (3) CH₃ (J=6.0); 1.03 t (6) CH₃(J=7.0); 1.10 to 1.73 m (2) CH₂ ; 2.60 q (4) CH₂ (J=7.0); 2.80 t (2)CH-N (J=5.2); 3.13 to 3.77 m (1) CH; 4.00 t (2) OCH₂ (J=5.2); 4.87 d (1)CH--C═O (J=11.8); 6.80 d (2) aromatic H (J=9.0); 7.00 to 7.60 m (10)aromatic H; 7.80 d (2) aromatic H (J=9.0).

EXAMPLE 3 Preparation oferythro-2,3-diphenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-pentanone

30.9 g (0.1 mole)2-phenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-ethanone (meltingpoint 77° to 78° C. from petroleum ether) are prepared in a mannersimilar to Example 1(a), and reacted as described in Example 1(c).Colorless crystals with a melting point of 128° C. (ether) result;yield: 12.8 g (30%).

R_(f) =0.35 (CHCl₃ /MeOH) (9/1).

C₂₉ H₃₃ NO₂ (427.6) Calculated: C 81.46 H 7.78 N 3.28. Determined: C81.32 H 7.80 N 3.17.

Molecular weight: 427 (determined by mass spectrometry).

IR spectrum (KBr): ν (C═O) 1669 cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.57 t (3) CH₃ (J=6.0); 1.13 to 1.73 m (2) CH₂; 1.77 to 1.97 m (4) CH₂ ; 2.37 to 2.73 m (4) CH₂ ; 2.87 t (2) CH₂(J=5.2); 3.20 to 3.77 m (1) CH; 4.03 t (2) OCH₂ (J=5.2); 4.90 d (1)CH--C═O (J=11.8); 6.80 d (2) aromatic H (J=9.0); 7.00 to 7.57 m (10)aromatic H; 7.80 d (2) aromatic H (J=9.0).

EXAMPLE 4 Preparation oferythro-2,3-diphenyl-1-(4'-(2-piperidin-1-yl-ethoxy)-phenyl)-1-pentanone

32.3 g (0.1 mole)2-phenyl-1-(4'-2-piperidin-1-yl-ethoxy)-phenyl)-1-ethanone (meltingpoint 73° C. from petroleum ether), prepared in a manner similar toExample 1(a), are reacted as described in Example 1(c). Colorlesscrystals with a melting point of 125° C. (petroleum ether) result;yield=40%. R_(f) =0.60 (CHCl₃ /MeOH (7/3)).

C₃₀ H₃₅ NO₂ (441.6) Calculated: C 81.59 H 7.99 N 3.17. Determined: C81.47 H 7.87 N 3.05.

Molecular weight: 441 (determined by mass spectrometry).

IR spectrum (KBr): ν (C═O) 1669 l cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.57 t (3) CH₃ (J=6.0); 1.10 to 1.83 m (8) CH₂; 2.30 to 2.70 m (4) CH₂ ; 2.73 t (2) CH₂ -N (J=5.2); 3.17 to 3.73 m (1)CH; 4.07 t (2) OCH₂ (J=5.2); 4.87 d (1) CH--C═O (J=11.8); 6.73 d (2)aromatic H (J=9.0); 6.90 to 7.57 m (10) aromatic H; 7.77 d (2) aromaticH (J=9.0).

EXAMPLE 5 Preparation oferythro-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2-(4'-methoxyphenyl)-3-phenyl-1-pentanone

31.3 g (0.1 mole)1-(4'-(2-dimethylaminoethoxy)-phenyl)-2-(4'-methoxyphenyl)-1-ethanone(melting point 75° to 77° C. from petroleum ether), prepared in a mannersimilar to Example 1(a) from 20.2 g (0.1 mole)N,N-dimethyl-2-phenoxyethylamine hydrochloride and 18.5 g (0.1 mole)4-methoxyphenylacetic acid chloride, are reacted as described in Example1(c). Colorless crystals with a melting point of 88° to 89° C.(petroleum ether) are recovered in a yield of 5.6 g (13%). R_(f) =0.25(CHCl₃ /MeOH (9/1)).

C₂₈ H₃₃ NO₃ (431.6) Calculated: C 77.93 H 7.71 N 3.25. Determined: C77.92 H 7.65 N 3.18.

Molecular weight: 431 (determined by mass spectrometry).

IR spectrum (KBr): ν (C═O) 1165 cm⁻¹.

¹ H-NMR spectrum (d₆ -acetone): 0.58 t (3) CH₃ (J=6.0); 1.10 to 1.73 m(2) CH₂ ; 2.20 s (6) N(CH₃)₂ ; 2.60 t (2) CH₂ --N (J=5.6); 3.13 to 3.73m (1) CH; 3.74 s (3) OCH₃ ; 4.07 t (2) OCH₂ (J=5.6); 5.20 d (1) CH--C═O(J=11.6); 6.70 to 8.13 m (13) aromatic H.

EXAMPLE 6 Preparation oferythro-1-(4'-(2-diethylaminoethoxy)-phenyl)-2-(4'-methoxyphenyl)-3-phenyl-1-pentanone

34.1 g of1-(4'-(2-diethylaminoethoxy)-phenyl)-2-(4'-methoxyphenyl)-1-ethanone(melting point 52° to 53° C., from petroleum ether), prepared in amanner similar to Example 1(a) and Example 5, are reacted as describedin Example 1(c). Colorless crystals with a melting point of 89°-90° C.(methanol/water) are recovered; R_(f) 0.35 (CHCl₃ /MeOH)); yield: 3.2 g(7%).

C₃₀ H₃₇ NO₃ (459.6) Calculated: C 78.40 H 8.11 N 3.05. Determined: C78.22 H 8.07 N 2.92.

Molecular weight: 459 (determined by mass spectrometry).

IR spectrum (KBr): ν (C═O) 1660 cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.57 t (3) CH₃ (J=6.2); 1.00 t (6) CH₃(J=7.0); 1.13 to 1.73 m (20 CH₂ ; 2.57 q (4) CH₂ (J=7.0); 2.77 t (2) CH₂--N (J=5.0); 3.03 to 3.67 m (1) CH; 3.73 s (3) OCH₃ ; 3.97 t (2) OCH₂(J=5.0); 4.77 d (1) CH--C═O (J=11.8); 6.53 to 7.90 m (13) aromatic H.

EXAMPLE 7 Preparation oferythro-2-(4'-methoxyphenyl)-3-phenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-pentanone

33.9 g (0.1 mole)2-(4'-methoxyphenyl)-1-(4'-2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-ethanone(melting point 71°-72° C., from petroleum ether) prepared in a mannersimilar to Example 1(a) and Example 5, are reacted as in Example 1(c).Colorless crystals with a melting point of 96°-98° C. (petroleumether/ether) are recovered in a yield of 11.9 g (26%). R_(f) 0.25 (CHCl₃/MeOH (9/1)).

C₃₀ H₃₅ NO₃ (457.6) Calculated: C 78.74 H 7.71 N 3.06. Determined: C78.89 H 7.69 N 3.15.

Molecular weight: 431 (determined by mass spectrometry).

IR spectrum (KBr): ν (C═O) 1669 cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.6 t (3) CH₃ (J=6.0); 1.10 to 1.73 m (2) CH₂; 1.60 to 2.00 m (4) CH₂ ; 2.37 to 2.73 m (4) CH₂ ; 2.87 t (2) CH--N(J=5.4); 3.10 to 3.73 m (1) CH; 3.80 s (3) OCH₃ ; 4.07 t (2) OCH₂(J=5.4); 4.83 d (1) CH--C═O (J=11.8); 6.63 to 7.97 m (13) aromatic H.

EXAMPLE 8 Preparation oferythro-2-(4'-methoxyphenyl)-3-phenyl-1-(4'-(2-piperidin-1-yl-ethoxy)-phenyl)-1-pentanone

35.3 g (0.1 mole)2-(4'-methoxyphenyl)-1-(4'-2-piperidin-1-yl-ethoxy)-phenyl)-1-ethanone(melting point 81° C. from ethanol) prepared in a manner similar toExample 1(a) and Example 5, are reacted as described in Example 1(c).Colorless crystals with a melting point of 98° to 99° C. (petroleumether/ether) are recovered; yield: 7.5 g (16%); R_(f) (CHCl₃ /MeOH(9/1)).

C₃₁ H₃₇ NO₃ (471.6).

Molecular weight: 471 (determined by mass spectrometry).

IR spectrum (Br): ν (C═O) 1667 cm⁻¹.

¹ H-NMR spectrum (CDCl₃): 0.58 t (3) CH₃ (H=6.2); 1.10 to 1.77 m (8) CH₂; 2.27 to 2.60 m (4) CH₂ ; 2.70 t (2) CH₂ --N (J=5.4); 3.07 to 3.73 m(1) CH; 3.75 s (3) OCH₃ ; 4.07 t (2) OCH₂ (J=5.4); 4.83 d (1) OHC═O(J=11.8); 6.57 to 7.93 m (13) aromatic H.

EXAMPLE 9 Preparation oferythro-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2-(4'-hydroxyphenyl)-3-phenyl-1-pentanone

43.2 g (0.1 mole)erythro-1-(4'-2-dimethylaminoethoxy)-phenyl)-2-(4'-methoxyphenyl)-3-phenyl-1-pentanonewere heated with 400 ml 48% aqueous solution of hydrobromic acid for 2hours under reflux. Subsequently, the solution is condensed to drynessunder vacuum, the residue made basic with approximately 200 ml of adilute aqueous ammonia solution and extracted three times with 100 mlaliquots of ethylacetate. The organic phase is washed with water toneutral pH and the solvent removed after drying over sodium sulfate. Theresidue is crystallized from methanol several times. Colorless crystalswith a melting point of 200° C. are recovered in a yield of 2.46 g(59%); R_(f) =0.20 (CHCl₃ /CH₃ OH (7/3)).

C₂₇ H₃₁ NO₃ (417.5) Calculated: C 77.67 H 7.48 N 3.35. Determined: C77.66 H 7.51 N 3.23.

Molecular weight: 417 (determined by mass spectrometry).

IR spectrum (KBr): ν (O--H) 3600 to 3100 cm⁻¹. ν (C═O) 1670 cm⁻¹.

¹ H-NMR spectrum (d₆ -acetone): 0.57 t (3) CH₃ (J=6.0); 1.17 to 1.67 m(2) CH₂ ; 2.20 s (6) N(CH₃)₂ ; 2.63 t (2) CH₂ N (J=5.0); 2.83 to 3.67 m(1) CH (J=5.0); 4.10 t (2) OCH₂ (J=5.0); 5.17 d (1) CH--C═O (J=11.8);6.67 to 8.17 m (13) aromatic H.

EXAMPLE 10 Preparation oferythro-2-(4'-hydroxyphenyl)-3-phenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-pentanone

45.7 g (0.1 mole)erythro-2-(4'-methoxyphenyl)-3-phenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-pentanoneare subjected in a manner similar to Example 9 to a partial ethercleavage and processed accordingly. Colorless crystals with a meltingpoint of 181°-182° C. (methanol) are recovered; yield: 18.1 g (41%).R_(f) =0.35 (CHCl₃ /CH₃ OH (7/3)).

C₂₉ H₃₃ NO₃ (443.6).

Molecular weight: 443 (determined by mass spectrometry).

IR spectrum (KBr): ν (O--H) 3600 to 3100 cm⁻¹. ν (C═O) 1669 cm⁻¹.

¹ H-NMR spectrum (CDCl₃ /d₆ -DMSO (4/1)): 0.57 t (3) CH₃ (J=6.0); 1.17to 1.93 m (2) CH₂ ; 1.77 m (4) CH₂ ; 2.57 m (4) CH₂ NCH₂ ; 2.83 t (2)CH₂ (J=5.0); 3.07 to 3.60 m (1) CH; 4.07 t (2) OCH₂ (J=5.0); 4.83 d (1)CH--C═O (J=11.8); 6.57 to 7.90 m (13) aromatic H; 8.77 wide (1) OH(interchangeable with D₂ O).

EXAMPLE 11 Preparation oferythro-2-(4'-methoxyphenyl)-3-phenyl-1-(4'-(2-pyrrolidin-1-yl-ethoxy)-phenyl)-1-pentanonecontaining medicine

20 g of a powdered active ingredient are mixed with 40 g lactose and 140g starch, and subsequently intermixed with 33 g talcum and 13 g calciumstearate. After careful mixing, the composition is filled into 2000 hardgelatine capsules of a suitable size, each capsule containing 10 mg ofthe active ingredient.

EXAMPLE 12 Preparation oferythro-1-(4'-(2-dimethylaminoethoxy)-phenyl)-2-(4'-hydroxyphenyl)-3-phenyl-1-pentanonecontaining medicine

20 g of a finely powdered active ingredient are mixed with 111 gmannitol, 15 g corn starch, and 6 g alginic acid and granulated. Thedried granulate is mixed carefully with 0.75 g methyl cellulose and 1.5g magnesium stearate, and pressed into 1000 tablets, so that each tabletcontains 20 mg of the active ingredient.

Pharmacological Investigations

(a) Bonding affinity to the estradiol receptor

The measurement of the bonding affinity to the estradiol receptor wasaffected by the method of N. Devleeschouwer, G. Leclercq, A. Danguy andJ. C. Heuson, (Europ. J. Cancer, 14, 721-723 (1978)). The uterus cytosalof female, prepubertal, white rabbits (New Zealand) weighing 2 kg, wasincubated for 18 hours at 40° C. with 2.5×10⁻⁹ M (³ H) estradiol, withthe further addition of unmarked estradiol (control) or the testsubstance in different concentrations. The bonding affinity to theestradiol receptor is expressed by the concentration of unmarkedestradiol (control) or the test substance added to the uterus cytosol,which effects a 50% displacement of the (³ H) estradiol bound to theestradiol receptor.

                  TABLE 2                                                         ______________________________________                                        Bonding Affinity of Test Substances                                            ##STR13##                                                                    No. of Compound                                                                             R.sup.1    R.sup.2 ED.sub.50 * (M)                              ______________________________________                                        Estradiol (control)                                                                         --         --      1.3 × 10.sup.-9                        1             (CH.sub.3).sub.2 N                                                                       H       6.0 × 10.sup.-6                        2             (C.sub.2 H.sub.5).sub.2 N                                                                H       4.0 × 10.sup.-6                                       ##STR14## H       6.0 × 10.sup.-6                        4                                                                                            ##STR15## H       2.8 × 10.sup.-6                        5             (CH.sub.3).sub.2 N                                                                       OCH.sub.3                                                                             4.5 × 10.sup.-6                        6             (C.sub.2 H.sub.5).sub.2 N                                                                OCH.sub.3                                                                             5.0 × 10.sup.-7                        7                                                                                            ##STR16## OCH.sub.3                                                                             1.1 × 10.sup.-6                        8                                                                                            ##STR17## OCH.sub.3                                                                             1.2 × 10.sup.-9                        9             (CH.sub.3).sub.2 N                                                                       OH      5.4 × 10.sup.-9                        10                                                                                           ##STR18## OH      8.0 × 10.sup.-8                        ______________________________________                                         *Concentration of substance displacing 50% (.sup.3 H) estradiol from the      estradiol receptor.                                                      

(b) Antiuterotropic Effect

The antiuterotropic effect was determined by a modified Dorfman test (R.I. Dorfman, "Methods in Hormone Research II" p. 707, Academic Press, NewYork-London, 1962), on sexually mature female Spraque-Dawley rats.

The test compounds were taken up in a 0.25% aqueous agar suspension andadministered by esophageal tube over a period of 21 days, six times perweek. Following the completion of the experiment, the uterus weight ofanimals treated with the active ingredient was related to the uterusweight of the control animals, which received only an empty agarsuspension.

                  TABLE 3                                                         ______________________________________                                        Antiuterotropic Activity of Test Substances                                             No. of                Weight of uterus                                        experimental                                                                             Dose       compared to                                   Compound No.                                                                            animals    mg/kg/day  control animals                               ______________________________________                                        2         10         3          -54%                                          3         10         3          -36%                                          4         10         3          -28%                                          5         10         3          -47%                                          7         10         3          -43%                                          9         10         3          -54%                                          ______________________________________                                    

(c) Mammatumor Inhibiting Effect

The tumor inhibiting effect was determined on the model of mammatumorsinduced by means of 7,12-dimethylbenz(a)anthracene of femaleSpraque-Dawley rats (Hannover strain), by the method of M. J. Golder(Europ. J. Cancer 11, 571 (1975)) and D. P. Griswold et al. (CancerResearch 26, 2169 (1966)).

The test substance were taken up in a 0.25% agar solution andadministered by esophageal tube over a period of 28 days, six times perweek. Twice weekly and on the 28th day of the experiment, the number ofanimals was ascertained and the tumor surface (mm² /animal) of thetherapy and control animals measured. At the completion of theexperiment, the percentage increase of the average tumor surface of thetreated animals was determined, compared with the control animals, whichwere valued at 100%.

                  TABLE 4                                                         ______________________________________                                        Tumor Inhibiting Effect of Test Substances                                               Number of            Relative Increase                                        experimental                                                                             Dose      of average                                    No. of Compound                                                                          animals    mg/kg/day tumor surface                                 ______________________________________                                        Empty control                                                                            10         --        100%                                          1          10         3         53%                                           9          10         3         30%                                           ______________________________________                                    

While the invention has been described in terms of various preferredembodiments, one skilled in the art will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims.

What is claimed is:
 1. An erythro-1,2,3-triphenyl-1-pentanone compoundhaving the formula: ##STR19## wherein R¹ is a dimethylamino group, andR² is a hydroxy group, and its pharmacologically acceptable salts.
 2. Apharmaceutical composition comprising a compound as claimed in claim 1in a pharmacologically acceptable carrier.
 3. The composition of claim 2wherein said composition is adapted for oral use.
 4. The composition ofclaim 3 in tablet, capsule, or dragee form.
 5. The composition of claim3 in the form of a suspension.
 6. The composition of claim 3, in dosageunit form in which each dosage unit contains a tumor inhibitingeffective amount of said compound.
 7. The composition of claim 6, indosage unit form in which each dosage unit contains from about 0.01 toabout 0.2 g of said compound.
 8. The composition of claim 7, in whicheach dosage unit contains about 0.02 to about 0.1 g of said compound. 9.A method of inhibiting hormone-dependent tumors which comprises the stepof administering a tumor-inhibiting effective amount of a compound asclaimed in claim 1.